Cigarette smoking has been verified to be one of the most important etiological factors causing the development of bronchogenic carcinoma and chronic obstructive pulmonary disease. Azithromycin (AZM) has been demonstrated to have antioxidant capacity. In the present study, whether AZM is able to attenuate cigarette smoke extract (CSE)‑induced A549 cell oxidative stress injury was investigated. Cells were incubated with CSE in the presence or absence of AZM. Cell viability was measured using a 3‑(4,5‑dimethylthiazol‑2‑yl)‑2,5‑diphenyltetrazolium bromide assay. The expression of vascular endothelial growth factor (VEGF) was analyzed using western blotting and ELISA. The expression of epithelial cell structural proteins, zona occludens (ZO)‑1 and occludin was determined using western blotting and immunofluorescence staining. Reactive oxygen species (ROS) production was examined by flow cytometry and fluorescence staining. The results demonstrated that the exposure of A549 cells to CSE decreased cell viability in a dose‑ and time‑dependent manner. AZM significantly attenuated the CSE‑induced decreases in the expression of VEGF and epithelial cell structural proteins, including ZO‑1 and occludin. CSE also stimulated ROS production in the A549 cell, while AZM significantly reversed the effects of CSE. In addition, the inhibition of ROS by N‑acetyl‑L‑cysteine had similar effects as AZM on the expression of VEGF and epithelial cell structural proteins and also enhanced cell proliferation. In conclusion, AZM attenuated CSE‑induced oxidative stress injury in A549 cells and may be a promising therapeutic agent for smoking‑associated pulmonary diseases.